Marianne R Spalinger , Stephanie Kasper , Claudia Gottier , Silvia Lang , Kirstin Atrott , Stephan R Vavricka , Sylvie Scharl , Petrus M Gutte , Markus G Grütter , Hans-Dietmar Beer , Emmanuel Contassot , Andrew C Chan , Xuezhi Dai , David J Rawlings , Florian Mair , Burkhard Becher , Werner Falk , Michael Fried , Gerhard Rogler , Michael Scharl
May 2 2016
Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.